Colesevelam hydrochloride is a bile acid sequestrant with a high capacity for binding bile acids. It has been shown to reduce total and low-density lipoprotein cholesterol levels. Colesevelam hydrochloride has been approved by FDA and is sold under the brand name Welchol®, as the only medicine with a single active ingredient to lower both blood sugar and “bad” cholesterol (LDL-C) in adults with Type 2 diabetes and high cholesterol. Welchol® is administered orally.
Colesevelam hydrochloride is a modified cross-linked polyallylamine polymer containing polyallylamine base moiety having a CH2—CHOH—CH2 group between two amino groups, N-alkylated with a specific ratio of 6-trimethylammoniumhexyl group and decyl group. Colesevelam hydrochloride has almost all of its free amines protonated and contains about 21% chloride by weight.
All prior art requires that Colesevelam be manufactured by crosslinking polyallylamine hydrochloride (PAA-HCl) with epichlorohydrin to form sevelamer first, which is then alkylated with 1-bromodecane (a.k.a., n-decyl bromide) and 6-bromohexyl trimethylammonium bromide (6-BHTAB) in a reaction medium to form colesevelam. The chloride form of sevelamer has also been approved by FDA and is sold in the United States under the brand name Renagel®. Renagel® is indicated for the control of serum phosphorus in patients with chronic kidney disease on dialysis.
U.S. Pat. No. 5,693,675 was the first patent that discloses the preparation of colesevelam. The process consists of cross-linking polyallylamine hydrochloride with epichlorohydrin, followed by alkylating the resulting cross-linked polyallylamine with 6-bromohexyl trimethylammonium and 1-bromodecane. Colesevelam thus obtained is dried in a vacuum oven at 50° C. and milled to pass through an 80 mesh sieve. The patent does not disclose the preparation of colesevelam HCl.
In U.S. Pat. No. 5,607,669, cross-linked polyallylamine (sevelamer) is prepared in situ and presented in a gelled form. The alkylation is carried out on the gelled cross-linked polyallylamine with 6-bromohexyl trimethylammonium bromide and n-decyl bromide in presence of an aqueous base or a methanolic solution of a base. The resulting polymer (colesevelam) is washed several times with methanol, 2M sodium chloride solution in water, and deionized water. The patent does not provide information regarding the preparation of colesevelam HCl.
U.S. Pat. No. 7,105,631 discloses a preparation of colesevelam by cross-linking polyallylamine hydrochloride with epichlorohydrin to give a cross-linked polymer gel (sevelamer) which is cut into defined shape and washed with methanol. The obtained wet crude gel is then alkylated in methanol by adding one or/and more alkylators at 5-90° C. and under pressure of 1-3 bars in presence of a base followed by reprotonation using a concentrated hydrochloric acid to give a crude colesevelam hydrochloride. The crude colesevelam hydrochloride is washed several times with methanol, 2M sodium chloride solution in water to form colesevelam hydrochloride.
U.S. Pat. No. 7,148,319 discloses a process for the preparation of colesevelam by first deprotonating of a cross-linked polymer gel (sevelamer) with a base, followed by washing with water, an organic solvent or an organic solvent/water mixture, then alkylating with one or more alkylators to give a gel suspension (colesevelam). Later, the gel suspension is reprotonated by means of a concentrated hydrochloric acid to form colesevelam hydrochloride.
U.S. Pat. No. 8,710,154 (also published as WO 2010/029579) discloses a process for the preparation of colesevelam hydrochloride by neutralizing polyallylamine hydrochloride to polyallylamine followed by cross-linking with epichlorohydrin in a non aqueous medium to obtain a cross-linked polymer (sevelamer). The cross-linked polymer is then alkylated to give colesevelam.
PCT publication WO 2010/041268 discloses a process for the preparation of colesevelam hydrochloride by the alkylation of sevelamer hydrochloride using 6-bromohexyltrimethyl ammonium bromide and n-decyl bromide in the presence of a methanol solution of sodium hydroxide to give colesevelam in a wet form, which is then treated with a dilute hydrochloric acid to form colesevelam hydrochloride.
In addition to the above prior art references, colesevelam hydrochloride has also been described in U.S. Pat. Nos. 5,624,963, 5,679,717, 5,917,007, 5,919,832, and 8,404,784, which are incorporated by references.
Most of the prior art processes are limited to a lab or pilot plant scale. One reason is that cross-linked polyallylamine polymers are water swellable. Upon isolation from water, these polymers swell and occupy a large volume of about at least 5 times the volume of the dry material. This makes the manufacturing process that involves treating the cross-linked polyallylamine with water a difficult task because of the large volumes and the requirement of unusually large capacities of manufacturing equipments. Each step of treatment with water makes the process more complicated. In the prior art, an organic solvent is used as a medium for alkylating the swollen polymer. Yet it is still the operation is still cumbersome. Therefore, there exists a need in the industry to provide an efficient and industrially viable process for the preparation of colesevelam hydrochloride.